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Novel Immunotherapy Approaches
Suresh S. Ramalingam, MDProfessor of Hematology and Medical Oncology
Assistant Dean for Cancer ResearchEmory University School of Medicine
Deputy Director, Winship Cancer Institute
Disclosures
• Scientific advisory board meetings
– Astra Zeneca, Amgen, Abbvie, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Lilly, Genentech, Merck, Novartis.
Immune Recognition
Yao S, et al. Nat Rev Drug Discov. 2013;12(2):130-146.
Antitumor Effects
Yao S, et al. Nat Rev Drug Discov. 2013;12(2):130-146.
T-Cell Immune Checkpoints as Targets for Immunotherapy
Mellman I et al. Nature. 2011;480:481–489.
CTLA-4
PD-1
TIM-3
BTLA
VISTA
LAG-3HVEM
CD27
CD137
GITR
OX40
CD28
T cellstimulation
Blockingantibodies
Agonisticantibodies
Inhibitoryreceptors
Activatingreceptors
T cell
B7-1
T cell
Other Combinations
Cully et al, Nature Rev Drug Disc, 2015
IDO/TDO Inhibitors
Nature Biotechnology, 2015
Role of IDO1 in Immune Regulation
1. Moretti et al. J Clin Endocrinol Metab. 2014:jc20133351; 2. Yu et al. Clin Dev Immunol. 2011;2011:469135; 3. Uyttenhove et al. Nat Med. 2003; 9(10):1269-1274; 4. Munn et al. J Clin Invest. 2007;117(5):1147-1154; 5. Godin-Ethier et al. Clin Cancer Res. 2011;17(22):6985-6991; 6. Spranger et al. J Immunother Cancer. 2014 Feb 18;2:3.
Epacadostat + Pembrolizumab
Gangadhar et al, Annual SITC Mtg, 2015
Baseline Characteristics
Efficacy
Anti-cancer Activity
• No grade 4 events• DLT: rash, transaminitis, neurotoxicity
T-Cell Immune Checkpoints as Targets for Immunotherapy
Mellman I et al. Nature. 2011;480:481–489.
CTLA-4
PD-1
TIM-3
BTLA
VISTA
LAG-3HVEM
CD27
CD137
GITR
OX40
CD28
T cellstimulation
Blockingantibodies
Agonisticantibodies
Inhibitoryreceptors
Activatingreceptors
T cell
B7-1
T cell
Targeting OX40
Infante et al, ASCO 2016
MOXR0916 + Atezolizumab
Infante et al, ASCO 2016
Anti-Cancer Activity
Infante et al, ASCO 2016
Induction of PDL-1 Expression
Infante et al, ASCO 2016
MOXR0916 + Atezo: Conclusions
• Combination was tolerated well
– Minimal grade 3/4 toxicity
• 300 mg/iv Q 21 days is the recommended dose
• PDL-1 induction was observed in tumor biopsy following OX40 activation
• Further evaluation is ongoing
T-Cell Immune Checkpoints as Targets for Immunotherapy
Mellman I et al. Nature. 2011;480:481–489.
CTLA-4
PD-1
TIM-3
BTLA
VISTA
LAG-3HVEM
CD27
CD137
GITR
OX40
CD28
T cellstimulation
Blockingantibodies
Agonisticantibodies
Inhibitoryreceptors
Activatingreceptors
T cell
B7-1
T cell
Varlilumab + Nivolumab: Phase 1 Study
• Varlilumab is a fully human agonist IgG1k antibody targeting CD27
• Phase 1 study in combination with Nivolumab
Sanborn et al, AACR 2016
Tolerability Profile
Sanborn et al, AACR 2016
Changes in Circulating Lymphocytes
Sanborn et al, AACR 2016
PD Evaluation in Paired Tumor Biopsies
Sanborn et al, AACR 2016
Conclusions
• Several promising targets to modulate T-cell responses
• Agents targeting co-stimulatory and co-inhibitory signals are in development
• Combination studies provide promising data regarding target modulation and induction of enhanced anti-tumor immunity